Isolated in 1997 from an Okinawan marine sponge, nakadomarin A is a highly complex and unprecedented hexacyclic alkaloid derived from the manzamine family of natural products. In addition to its intriguing molecular architecture, nakadomarin A has exhibited very promising biological activities including antitumor, antifungal, and antimicrobial properties. Unfortunately, the insufficient availability of the alkaloid natural product (only 6.0 mg isolated from 1.0 kg of wet sponge) has limited further biological evaluation of the therapeutic effects. Synthetic methods and routes toward nakadomarin A are currently inefficient, thus a more concise synthesis is necessary. The focus of this proposal is the development of an efficient and enantioselective total synthesis of nakadomarin A. To achieve this goal, the diastereoselective [3+2] cycloaddition of butenolide-derived azomethine ylides will be developed (Specific Aim 1). Simple model studies will be devised to rapidly investigate this proposed strategy. The development of a concise and versatile synthesis of nakadomarin A will generate ample material allowing for extensive biological evaluation of the alkaloid natural product (Specific Aim 2). Also, intermediates prepared during the synthesis will comprise a collection of distinct molecular scaffolds for further biological study. Through a collaboration with the state-of-the-art high through put screening facility (HTS) established at Memorial Sloan-Kettering Cancer Center, nakadomarin A and the library of intermediates developed during the proposal period will be tested against a panel of known cancer cell lines. PUBLIC HEALTH RELEVANCE: Nakadamorin A is an unprecendented marine-derived natural product exhibiting promising biological activities including antitumor, antifungal, and antimicrobial properties. The development of a concise and efficient chemical synthesis of nakadomarin A will facilitate its use as a biochemical probe and cancer therapeutic agent, as well as allow for the generation of nonnatural analogues for drug discovery.